Epstein-Barr virus (EBV) causes infectious mononucleosis in adolescents and malignant B lymphocyte proliferation in AIDS patients and patients undergoing immune suppression for organ transplantation. EBV is etiologically associated with African Burkitt's lymphoma and nasopharyngeal carcinoma. In vitro, EBV transformed, latently infected B lymphocytes contain EBV epsisomes and nine virus encoded proteins. Six are nuclear proteins (EBNAs) and three are the integral membrane proteins, LMP1, LMP2A, and LMP2B. These nine proteins are presumed to mediate latent virus infection or B. lymphocyte proliferation and thus are under intense investigation. Besides EBNA1, which is required for episome maintenance, LMP1 and LMP2A are the latently expressed proteins consistently detected in EBV related malignancies, and the EBNA1 and LMP2A messages are the only EBV- specific messages detected in PCR analysis of B lymphocytes from individuals harboring latent EBV infections. Nasopharyngeal carcinoma (NPC) occurs worldwide but is characterized by marked geographical and population differences in incidence. While rare among Europeans and North American Caucasians, NPC develops with high incidence in southern China and southeast Asia where it may represent 25 percent of all cancers. The tumor also occurs with increased incidence in other Chinese populations, Alaskan Eskimos, and Mediterranean Africans. NPC has been classified into three types: squamous cell carcinoma (SCC), nonkeratinizing carcinoma (NKC), and undifferentiated carcinoma (UC). Recent reports indicate that all forms of NPC are uniformly infected with clonal populations of EBV genomes. In all forms of NPC, the same set of EBV genes are expressed namely LMP1, LMP2A, and EBNA1. This research grant proposes to analyze the role of EBNA1, LMP1, and LMP2A in the pathogenesis of NPC and may prove informative for other EBV-associated malignancies. In the four Specific Aims, we propose to analyze the in vitro phenotype of keratinocytes expressing EBNA1, LMP1, and LMP2A and to develop a transgenic model system to investigate the role of LMP2A in NPC and the possible cooperation with LMP1. Understanding the role of EBNA1, LMP1, and, LMP2A in NPC may suggest novel therapeutics for the treatment of NPC, and a better understanding of factors that can influence the development of oral cancers.